ID AIFM1_HUMAN Reviewed; 613 AA. AC O95831; A4QPB4; B1ALN1; B2RB08; D3DTE9; E9PRR0; Q1L6K4; Q1L6K6; Q2QKE4; AC Q5JUZ7; Q6I9X6; Q9Y3I3; Q9Y3I4; DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 27-MAR-2024, entry version 228. DE RecName: Full=Apoptosis-inducing factor 1, mitochondrial {ECO:0000305}; DE EC=1.6.99.- {ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, ECO:0000269|PubMed:27178839}; DE AltName: Full=Programmed cell death protein 8; DE Flags: Precursor; GN Name=AIFM1 {ECO:0000312|HGNC:HGNC:8768}; Synonyms=AIF, PDCD8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=9989411; DOI=10.1038/17135; RA Susin S.A., Lorenzo H.K., Zamzami N., Marzo I., Snow B.E., Brothers G.M., RA Mangion J., Jacotot E., Costantini P., Loeffler M., Larochette N., RA Goodlett D.R., Aebersold R., Siderovski D.P., Penninger J.M., Kroemer G.; RT "Molecular characterization of mitochondrial apoptosis-inducing factor."; RL Nature 397:441-446(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5), PROTEIN SEQUENCE OF N-TERMINUS, RP SUBCELLULAR LOCATION (ISOFORM 5), TISSUE SPECIFICITY (ISOFORM 5), FUNCTION RP (ISOFORM 5), AND INDUCTION BY GAMMA-IRRADIATION (ISOFORM 5). RX PubMed=16365034; DOI=10.1074/jbc.m509884200; RA Delettre C., Yuste V.J., Moubarak R.S., Bras M., Lesbordes-Brion J.-C., RA Petres S., Bellalou J., Susin S.A.; RT "AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with RT potential pathological relevance in human cancer."; RL J. Biol. Chem. 281:6413-6427(2006). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 6), ALTERNATIVE SPLICING, RP FUNCTION (ISOFORM 4), SUBCELLULAR LOCATION (ISOFORM 4), AND TISSUE RP SPECIFICITY (ISOFORMS 4 AND 6). RX PubMed=16644725; DOI=10.1074/jbc.m601751200; RA Delettre C., Yuste V.J., Moubarak R.S., Bras M., Robert N., Susin S.A.; RT "Identification and characterization of AIFsh2, a mitochondrial apoptosis- RT inducing factor (AIF) isoform with NADH oxidase activity."; RL J. Biol. Chem. 281:18507-18518(2006). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3). RA Rhodes S.; RL Submitted (APR-1999) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Kidney; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C., RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., RA Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP PROTEIN SEQUENCE OF 55-59, SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE. RX PubMed=15775970; DOI=10.1038/sj.emboj.7600614; RA Otera H., Ohsakaya S., Nagaura Z., Ishihara N., Mihara K.; RT "Export of mitochondrial AIF in response to proapoptotic stimuli depends on RT processing at the intermembrane space."; RL EMBO J. 24:1375-1386(2005). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 171-613. RC TISSUE=Brain; RA Mei G., Yu W., Gibbs R.A.; RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases. RN [12] RP REVIEW. RX PubMed=10913597; DOI=10.1016/s0014-5793(00)01731-2; RA Daugas E., Nochy D., Ravagnan L., Loeffler M., Susin S.A., Zamzami N., RA Kroemer G.; RT "Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase RT involved in apoptosis."; RL FEBS Lett. 476:118-123(2000). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH EIF3G. RX PubMed=17094969; DOI=10.1016/j.febslet.2006.10.049; RA Kim J.T., Kim K.D., Song E.Y., Lee H.G., Kim J.W., Kim J.W., Chae S.K., RA Kim E., Lee M.S., Yang Y., Lim J.S.; RT "Apoptosis-inducing factor (AIF) inhibits protein synthesis by interacting RT with the eukaryotic translation initiation factor 3 subunit p44 (eIF3g)."; RL FEBS Lett. 580:6375-6383(2006). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-105, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [15] RP UBIQUITINATION BY XIAP/BIRC4, AND INTERACTION WITH XIAP/BIRC4. RX PubMed=17967870; DOI=10.1128/mcb.01065-07; RA Wilkinson J.C., Wilkinson A.S., Galban S., Csomos R.A., Duckett C.S.; RT "Apoptosis-inducing factor is a target for ubiquitination through RT interaction with XIAP."; RL Mol. Cell. Biol. 28:237-247(2008). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-268, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [17] RP FUNCTION. RX PubMed=19418225; DOI=10.1007/s10495-009-0353-7; RA Son Y.O., Jang Y.S., Heo J.S., Chung W.T., Choi K.C., Lee J.C.; RT "Apoptosis-inducing factor plays a critical role in caspase-independent, RT pyknotic cell death in hydrogen peroxide-exposed cells."; RL Apoptosis 14:796-808(2009). RN [18] RP ALTERNATIVE SPLICING (ISOFORM 3), SUBCELLULAR LOCATION (ISOFORM 3), AND RP SUBUNIT. RX PubMed=20111043; DOI=10.1038/cdd.2009.211; RA Hangen E., De Zio D., Bordi M., Zhu C., Dessen P., Caffin F., Lachkar S., RA Perfettini J.L., Lazar V., Benard J., Fimia G.M., Piacentini M., Harper F., RA Pierron G., Vicencio J.M., Benit P., de Andrade A., Hoglinger G., RA Culmsee C., Rustin P., Blomgren K., Cecconi F., Kroemer G., Modjtahedi N.; RT "A brain-specific isoform of mitochondrial apoptosis-inducing factor: RT AIF2."; RL Cell Death Differ. 17:1155-1166(2010). RN [19] RP INTERACTION WITH PRELID1. RX PubMed=21364629; DOI=10.1038/cddis.2009.19; RA McKeller M.R., Herrera-Rodriguez S., Ma W., Ortiz-Quintero B., Rangel R., RA Cande C., Sims-Mourtada J.C., Melnikova V., Kashi C., Phan L.M., Chen Z., RA Huang P., Dunner K. Jr., Kroemer G., Singh K.K., Martinez-Valdez H.; RT "Vital function of PRELI and essential requirement of its LEA motif."; RL Cell Death Dis. 1:E21-E21(2010). RN [20] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [21] RP UBIQUITINATION AT LYS-255 BY XIAP/BIRC4. RX PubMed=22103349; DOI=10.1021/bi201483g; RA Lewis E.M., Wilkinson A.S., Davis N.Y., Horita D.A., Wilkinson J.C.; RT "Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X- RT linked inhibitor of apoptosis at a residue critical for AIF-mediated RT chromatin degradation."; RL Biochemistry 50:11084-11096(2011). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-105; SER-116; SER-268 AND RP SER-292, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-116; SER-118; SER-268; RP SER-371; THR-521; SER-524 AND SER-530, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [24] RP FUNCTION, INTERACTION WITH CHCHD4, SUBCELLULAR LOCATION, CHARACTERIZATION RP OF VARIANT COXPD6 GLU-308, AND CHARACTERIZATION OF VARIANT CMTX4 VAL-493. RX PubMed=26004228; DOI=10.1016/j.molcel.2015.04.020; RA Hangen E., Feraud O., Lachkar S., Mou H., Doti N., Fimia G.M., Lam N.V., RA Zhu C., Godin I., Muller K., Chatzi A., Nuebel E., Ciccosanti F., RA Flamant S., Benit P., Perfettini J.L., Sauvat A., Bennaceur-Griscelli A., RA Ser-Le Roux K., Gonin P., Tokatlidis K., Rustin P., Piacentini M., Ruvo M., RA Blomgren K., Kroemer G., Modjtahedi N.; RT "Interaction between AIF and CHCHD4 Regulates Respiratory Chain RT Biogenesis."; RL Mol. Cell 58:1001-1014(2015). RN [25] RP CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER MET-54, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PARP1. RX PubMed=33168626; DOI=10.1074/jbc.ra120.014479; RA Mashimo M., Onishi M., Uno A., Tanimichi A., Nobeyama A., Mori M., RA Yamada S., Negi S., Bu X., Kato J., Moss J., Sanada N., Kizu R., Fujii T.; RT "The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to RT induce AIF-mediated apoptosis."; RL J. Biol. Chem. 296:100046-100046(2021). RN [27] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 121-613 IN COMPLEX WITH FAD, RP SUBCELLULAR LOCATION, AND DNA-BINDING. RX PubMed=12198487; DOI=10.1038/nsb836; RA Ye H., Cande C., Stephanou N.C., Jiang S., Gurbuxani S., Larochette N., RA Daugas E., Garrido C., Kroemer G., Wu H.; RT "DNA binding is required for the apoptogenic action of apoptosis inducing RT factor."; RL Nat. Struct. Biol. 9:680-684(2002). RN [28] {ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6} RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 121-613 IN COMPLEX WITH FAD AND RP NAD, SUBUNIT, MUTAGENESIS OF 413-GLU--ARG-430, SUBCELLULAR LOCATION, RP COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, FAD-BINDING, NAD-BINDING, AND RP CATALYTIC ACTIVITY. RX PubMed=24914854; DOI=10.1021/bi500343r; RA Ferreira P., Villanueva R., Martinez-Julvez M., Herguedas B., Marcuello C., RA Fernandez-Silva P., Cabon L., Hermoso J.A., Lostao A., Susin S.A., RA Medina M.; RT "Structural insights into the coenzyme mediated monomer-dimer transition of RT the pro-apoptotic apoptosis inducing factor."; RL Biochemistry 53:4204-4215(2014). RN [29] {ECO:0007744|PDB:5FS6, ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, ECO:0007744|PDB:5FS9} RP X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) OF 103-613 IN COMPLEX WITH FAD, RP CHARACTERIZATION OF VARIANT SER-262, CHARACTERIZATION OF VARIANTS COXPD6 RP LEU-243; GLU-308 AND GLU-338, FUNCTION, DNA-BINDING, FAD-BINDING, CATALYTIC RP ACTIVITY, AND COFACTOR. RX PubMed=27178839; DOI=10.1016/j.jmb.2016.05.004; RA Sevrioukova I.F.; RT "Structure/Function Relations in AIFM1 Variants Associated with RT Neurodegenerative Disorders."; RL J. Mol. Biol. 428:3650-3665(2016). RN [30] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 103-613 IN COMPLEX WITH FAD, RP FUNCTION, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, DNA-BINDING, SUBUNIT, RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, VARIANT CMTX4 VAL-493, RP CHARACTERIZATION OF VARIANT CMTX4 VAL-493, AND CATALYTIC ACTIVITY. RX PubMed=23217327; DOI=10.1016/j.ajhg.2012.10.008; RA Rinaldi C., Grunseich C., Sevrioukova I.F., Schindler A., RA Horkayne-Szakaly I., Lamperti C., Landoure G., Kennerson M.L., RA Burnett B.G., Boennemann C., Biesecker L.G., Ghezzi D., Zeviani M., RA Fischbeck K.H.; RT "Cowchock syndrome is associated with a mutation in apoptosis-inducing RT factor."; RL Am. J. Hum. Genet. 91:1095-1102(2012). RN [31] {ECO:0007744|PDB:5KVH, ECO:0007744|PDB:5KVI} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 78-613 IN COMPLEX WITH FAD, RP SUBUNIT, MUTAGENESIS OF TRP-196; 443-TYR--ILE-445; HIS-454; TRP-477; RP SER-480; ASP-485; ARG-529; GLU-531; GLU-533 AND GLU-535, COFACTOR, AND RP FAD-BINDING. RX PubMed=27818101; DOI=10.1016/j.str.2016.09.012; RA Brosey C.A., Ho C., Long W.Z., Singh S., Burnett K., Hura G.L., Nix J.C., RA Bowman G.R., Ellenberger T., Tainer J.A.; RT "Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor."; RL Structure 24:2067-2079(2016). RN [32] RP VARIANT COXPD6 ARG-201 DEL, CHARACTERIZATION OF VARIANT COXPD6 ARG-201 DEL, RP AND FUNCTION. RX PubMed=20362274; DOI=10.1016/j.ajhg.2010.03.002; RA Ghezzi D., Sevrioukova I., Invernizzi F., Lamperti C., Mora M., D'Adamo P., RA Novara F., Zuffardi O., Uziel G., Zeviani M.; RT "Severe X-linked mitochondrial encephalomyopathy associated with a mutation RT in apoptosis-inducing factor."; RL Am. J. Hum. Genet. 86:639-649(2010). RN [33] RP VARIANT COXPD6 GLU-308. RX PubMed=22019070; DOI=10.1016/j.ymgme.2011.09.020; RA Berger I., Ben-Neriah Z., Dor-Wolman T., Shaag A., Saada A., Zenvirt S., RA Raas-Rothschild A., Nadjari M., Kaestner K.H., Elpeleg O.; RT "Early prenatal ventriculomegaly due to an AIFM1 mutation identified by RT linkage analysis and whole exome sequencing."; RL Mol. Genet. Metab. 104:517-520(2011). RN [34] RP INVOLVEMENT IN DFNX5, AND VARIANTS DFNX5 ALA-260; PHE-344; ARG-360; RP GLN-422; TRP-422; CYS-430; GLN-451; VAL-472; LEU-475; MET-498 AND MET-591. RX PubMed=25986071; DOI=10.1136/jmedgenet-2014-102961; RA Zong L., Guan J., Ealy M., Zhang Q., Wang D., Wang H., Zhao Y., Shen Z., RA Campbell C.A., Wang F., Yang J., Sun W., Lan L., Ding D., Xie L., Qi Y., RA Lou X., Huang X., Shi Q., Chang S., Xiong W., Yin Z., Yu N., Zhao H., RA Wang J., Wang J., Salvi R.J., Petit C., Smith R.J., Wang Q.; RT "Mutations in apoptosis-inducing factor cause X-linked recessive auditory RT neuropathy spectrum disorder."; RL J. Med. Genet. 52:523-531(2015). RN [35] RP VARIANT COXPD6 LEU-243, AND CHARACTERIZATION OF VARIANT COXPD6 LEU-243. RX PubMed=25583628; DOI=10.1016/j.mito.2015.01.001; RA Kettwig M., Schubach M., Zimmermann F.A., Klinge L., Mayr J.A., Biskup S., RA Sperl W., Gaertner J., Huppke P.; RT "From ventriculomegaly to severe muscular atrophy: Expansion of the RT clinical spectrum related to mutations in AIFM1."; RL Mitochondrion 21C:12-18(2015). RN [36] RP VARIANT SER-262, AND CHARACTERIZATION OF VARIANT SER-262. RX PubMed=25934856; DOI=10.1212/wnl.0000000000001613; RA Ardissone A., Piscosquito G., Legati A., Langella T., Lamantea E., RA Garavaglia B., Salsano E., Farina L., Moroni I., Pareyson D., Ghezzi D.; RT "A slowly progressive mitochondrial encephalomyopathy widens the spectrum RT of AIFM1 disorders."; RL Neurology 84:2193-2195(2015). RN [37] RP VARIANT COXPD6 GLU-338, AND CHARACTERIZATION OF VARIANT COXPD6 GLU-338. RX PubMed=26173962; DOI=10.1038/ejhg.2015.141; RA Diodato D., Tasca G., Verrigni D., D'Amico A., Rizza T., Tozzi G., RA Martinelli D., Verardo M., Invernizzi F., Nasca A., Bellacchio E., RA Ghezzi D., Piemonte F., Dionisi-Vici C., Carrozzo R., Bertini E.; RT "A novel AIFM1 mutation expands the phenotype to an infantile motor neuron RT disease."; RL Eur. J. Hum. Genet. 24:463-466(2016). RN [38] RP VARIANTS SEMDHL HIS-235; GLY-237 AND VAL-237, CHARACTERIZATION OF VARIANT RP SEMDHL HIS-235, INVOLVEMENT IN SEMDHL, AND TISSUE SPECIFICITY. RX PubMed=28842795; DOI=10.1007/s10048-017-0520-x; RA Miyake N., Wolf N.I., Cayami F.K., Crawford J., Bley A., Bulas D., RA Conant A., Bent S.J., Gripp K.W., Hahn A., Humphray S., Kimura-Ohba S., RA Kingsbury Z., Lajoie B.R., Lal D., Micha D., Pizzino A., Sinke R.J., RA Sival D., Stolte-Dijkstra I., Superti-Furga A., Ulrick N., Taft R.J., RA Ogata T., Ozono K., Matsumoto N., Neubauer B.A., Simons C., Vanderver A.; RT "X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) RT associated with mutations in AIFM1."; RL Neurogenetics 18:185-194(2017). CC -!- FUNCTION: Functions both as NADH oxidoreductase and as regulator of CC apoptosis (PubMed:20362274, PubMed:23217327, PubMed:17094969, CC PubMed:33168626). In response to apoptotic stimuli, it is released from CC the mitochondrion intermembrane space into the cytosol and to the CC nucleus, where it functions as a proapoptotic factor in a caspase- CC independent pathway (PubMed:20362274). Release into the cytoplasm is CC mediated upon binding to poly-ADP-ribose chains (By similarity). The CC soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. CC caspase-independent fragmentation of chromosomal DNA (PubMed:20362274). CC Binds to DNA in a sequence-independent manner (PubMed:27178839). CC Interacts with EIF3G, and thereby inhibits the EIF3 machinery and CC protein synthesis, and activates caspase-7 to amplify apoptosis CC (PubMed:17094969). Plays a critical role in caspase-independent, CC pyknotic cell death in hydrogen peroxide-exposed cells CC (PubMed:19418225). In contrast, participates in normal mitochondrial CC metabolism. Plays an important role in the regulation of respiratory CC chain biogenesis by interacting with CHCHD4 and controlling CHCHD4 CC mitochondrial import (PubMed:26004228). {ECO:0000250|UniProtKB:Q9Z0X1, CC ECO:0000269|PubMed:17094969, ECO:0000269|PubMed:19418225, CC ECO:0000269|PubMed:20362274, ECO:0000269|PubMed:23217327, CC ECO:0000269|PubMed:26004228, ECO:0000269|PubMed:27178839, CC ECO:0000269|PubMed:33168626}. CC -!- FUNCTION: [Isoform 4]: Has NADH oxidoreductase activity. Does not CC induce nuclear apoptosis. {ECO:0000269|PubMed:16644725}. CC -!- FUNCTION: [Isoform 5]: Pro-apoptotic isoform. CC {ECO:0000269|PubMed:16365034}. CC -!- CATALYTIC ACTIVITY: CC Reaction=A + H(+) + NADH = AH2 + NAD(+); Xref=Rhea:RHEA:11356, CC ChEBI:CHEBI:13193, ChEBI:CHEBI:15378, ChEBI:CHEBI:17499, CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; CC Evidence={ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, CC ECO:0000269|PubMed:27178839}; CC -!- CATALYTIC ACTIVITY: [Isoform 4]: CC Reaction=A + H(+) + NADH = AH2 + NAD(+); Xref=Rhea:RHEA:11356, CC ChEBI:CHEBI:13193, ChEBI:CHEBI:15378, ChEBI:CHEBI:17499, CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; CC Evidence={ECO:0000269|PubMed:16644725}; CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC Evidence={ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, CC ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.53 mM for NADH {ECO:0000269|PubMed:23217327}; CC KM=26 uM for cytochrome c (at pH 7.4 and 25 degrees Celsius) CC {ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:27178839}; CC KM=138 uM for dichlorophenolindophenol (at pH 7.4 and 25 degrees CC Celsius) {ECO:0000269|PubMed:27178839}; CC KM=0.51 mM for NADH (at pH 7.4 and 25 degrees Celsius) CC {ECO:0000269|PubMed:27178839}; CC KM=896 uM for NADPH {ECO:0000269|PubMed:24914854}; CC Note=kcat is 86 min(-1) for dichlorophenolindophenol reduction and 24 CC min(-1) for cytochrome c reduction (PubMed:27178839). kcat is 1.5 CC sec(-1) for dichlorophenolindophenol reduction, 3.1 sec(-1) for CC ferricyanide and 0.6 sec(-1) for cytochrome c reduction CC (PubMed:24914854). {ECO:0000269|PubMed:24914854, CC ECO:0000269|PubMed:27178839}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 4]: CC Kinetic parameters: CC KM=102.6 uM for NADH {ECO:0000269|PubMed:16644725}; CC KM=45.3 uM for NADPH {ECO:0000269|PubMed:16644725}; CC -!- SUBUNIT: Monomer (oxidized form). Homodimer (reduced form). Upon CC reduction with NADH, undergoes dimerization and forms tight, long-lived CC FADH2-NAD charge transfer complexes (CTC) resistant to oxidation CC (PubMed:24914854, PubMed:20111043, PubMed:23217327, PubMed:27818101). CC Also dimerizes with isoform 3 preventing its release from mitochondria CC (PubMed:20111043). Interacts with XIAP/BIRC4 (PubMed:17967870). CC Interacts (via N-terminus) with EIF3G (via C-terminus) CC (PubMed:17094969). Interacts with PRELID1 (PubMed:21364629). Interacts CC with CHCHD4; the interaction increases in presence of NADH CC (PubMed:26004228). Interacts with processed form of PARP1 (Poly [ADP- CC ribose] polymerase 1, processed C-terminus); interaction is mediated CC with poly-ADP-ribose chains attached to PARP1, promoting translocation CC into the nucleus (PubMed:33168626). {ECO:0000269|PubMed:17094969, CC ECO:0000269|PubMed:17967870, ECO:0000269|PubMed:20111043, CC ECO:0000269|PubMed:21364629, ECO:0000269|PubMed:23217327, CC ECO:0000269|PubMed:24914854, ECO:0000269|PubMed:26004228, CC ECO:0000269|PubMed:27818101, ECO:0000269|PubMed:33168626}. CC -!- INTERACTION: CC O95831; O75821: EIF3G; NbExp=9; IntAct=EBI-356440, EBI-366632; CC O95831; Q63ZY3: KANK2; NbExp=2; IntAct=EBI-356440, EBI-2556193; CC O95831; Q63ZY3-2: KANK2; NbExp=4; IntAct=EBI-356440, EBI-6244894; CC O95831; Q9Y3Q8: TSC22D4; NbExp=2; IntAct=EBI-356440, EBI-739485; CC O95831; Q5EP34: PA; Xeno; NbExp=8; IntAct=EBI-356440, EBI-25772799; CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space CC {ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:24914854, CC ECO:0000269|PubMed:26004228}. Mitochondrion inner membrane. Cytoplasm CC {ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:33168626}. Nucleus CC {ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:17094969, CC ECO:0000269|PubMed:33168626}. Cytoplasm, perinuclear region CC {ECO:0000269|PubMed:17094969}. Note=Proteolytic cleavage during or just CC after translocation into the mitochondrial intermembrane space (IMS) CC results in the formation of an inner-membrane-anchored mature form CC (AIFmit). During apoptosis, further proteolytic processing leads to a CC mature form, which is confined to the mitochondrial IMS in a soluble CC form (AIFsol). AIFsol is released to the cytoplasm in response to CC specific death signals, and translocated to the nucleus, where it CC induces nuclear apoptosis (PubMed:15775970). Release into the cytoplasm CC is mediated upon binding to poly-ADP-ribose chains (By similarity). CC Translocation into the nucleus is promoted by interaction with (auto- CC poly-ADP-ribosylated) processed form of PARP1 (PubMed:33168626). CC Colocalizes with EIF3G in the nucleus and perinuclear region CC (PubMed:17094969). {ECO:0000250|UniProtKB:Q9Z0X1, CC ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:17094969, CC ECO:0000269|PubMed:33168626}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Mitochondrion intermembrane space CC {ECO:0000269|PubMed:20111043}. Mitochondrion inner membrane CC {ECO:0000269|PubMed:20111043}. Note=Has a stronger membrane anchorage CC than isoform 1. {ECO:0000269|PubMed:20111043}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Mitochondrion CC {ECO:0000269|PubMed:16644725}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:16644725}. Note=In pro-apoptotic conditions, is CC released from mitochondria to cytosol in a calpain/cathepsin-dependent CC manner. {ECO:0000269|PubMed:16644725}. CC -!- SUBCELLULAR LOCATION: [Isoform 5]: Cytoplasm CC {ECO:0000269|PubMed:16365034}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=AIF; CC IsoId=O95831-1; Sequence=Displayed; CC Name=2; CC IsoId=O95831-2; Sequence=VSP_004357; CC Name=3; Synonyms=AIF-exB, AIF2; CC IsoId=O95831-3; Sequence=VSP_022953; CC Name=4; Synonyms=AIFsh2 {ECO:0000303|PubMed:16644725}; CC IsoId=O95831-4; Sequence=VSP_043637, VSP_043638; CC Name=5; Synonyms=AIFsh; CC IsoId=O95831-5; Sequence=VSP_046248; CC Name=6; Synonyms=AIFsh3 {ECO:0000303|PubMed:16644725}; CC IsoId=O95831-6; Sequence=VSP_060785, VSP_060786; CC -!- TISSUE SPECIFICITY: Expressed in all tested tissues (PubMed:16644725). CC Detected in muscle and skin fibroblasts (at protein level) CC (PubMed:23217327). Expressed in osteoblasts (at protein level) CC (PubMed:28842795). {ECO:0000269|PubMed:16644725, CC ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:28842795}. CC -!- TISSUE SPECIFICITY: [Isoform 3]: Brain specific. CC {ECO:0000269|PubMed:20111043}. CC -!- TISSUE SPECIFICITY: [Isoform 4]: Expressed in all tested tissues except CC brain. {ECO:0000269|PubMed:16644725}. CC -!- TISSUE SPECIFICITY: [Isoform 5]: Isoform 5 is frequently down-regulated CC in human cancers. {ECO:0000269|PubMed:16365034}. CC -!- INDUCTION: [Isoform 5]: Strongly down-regulated in many tumor cells, CC up-regulated by gamma-irradiation. {ECO:0000269|PubMed:16365034}. CC -!- PTM: Under normal conditions, a 54-residue N-terminal segment is first CC proteolytically removed during or just after translocation into the CC mitochondrial intermembrane space (IMS) by the mitochondrial processing CC peptidase (MPP) to form the inner-membrane-anchored mature form CC (AIFmit). During apoptosis, it is further proteolytically processed at CC amino-acid position 101 leading to the generation of the mature form, CC which is confined to the mitochondrial IMS in a soluble form (AIFsol). CC AIFsol is released to the cytoplasm in response to specific death CC signals, and translocated to the nucleus, where it induces nuclear CC apoptosis in a caspase-independent manner. CC {ECO:0000269|PubMed:15775970}. CC -!- PTM: Ubiquitination by XIAP/BIRC4 does not lead to proteasomal CC degradation. Ubiquitination at Lys-255 by XIAP/BIRC4 blocks its ability CC to bind DNA and induce chromatin degradation, thereby inhibiting its CC ability to induce cell death. {ECO:0000269|PubMed:17967870, CC ECO:0000269|PubMed:22103349}. CC -!- DISEASE: Combined oxidative phosphorylation deficiency 6 (COXPD6) CC [MIM:300816]: A mitochondrial disease resulting in a neurodegenerative CC disorder characterized by psychomotor delay, hypotonia, areflexia, CC muscle weakness and wasting. Some patients manifest prenatal CC ventriculomegaly and severe postnatal encephalomyopathy. CC {ECO:0000269|PubMed:20362274, ECO:0000269|PubMed:22019070, CC ECO:0000269|PubMed:25583628, ECO:0000269|PubMed:26004228, CC ECO:0000269|PubMed:26173962, ECO:0000269|PubMed:27178839}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Charcot-Marie-Tooth disease, X-linked recessive, 4, with or CC without cerebellar ataxia (CMTX4) [MIM:310490]: A neuromuscular CC disorder characterized by progressive sensorimotor axonal neuropathy, CC distal sensory impairment, difficulty walking due to peripheral CC neuropathy and/or cerebellar ataxia, and deafness due to auditory CC neuropathy. Additional features include cognitive impairment, CC cerebellar atrophy, dysarthria, abnormal extraocular movements, tremor, CC dysmetria and spasticity. The age at onset ranges from infancy to young CC adulthood. {ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:26004228}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Deafness, X-linked, 5, with peripheral neuropathy (DFNX5) CC [MIM:300614]: A form of hearing loss characterized by absent or CC severely abnormal auditory brainstem response, abnormal middle ear CC reflexes, abnormal speech discrimination, loss of outer hair cell CC function, and cochlear nerve hypoplasia. DFNX5 patients manifest CC auditory neuropathy with childhood onset, associated with distal CC sensory impairment affecting the peripheral nervous system. CC {ECO:0000269|PubMed:25986071}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spondyloepimetaphyseal dysplasia, X-linked, with CC hypomyelinating leukodystrophy (SEMDHL) [MIM:300232]: An X-linked CC recessive developmental disorder characterized by slowly progressive CC skeletal and neurologic abnormalities, including short stature, large CC and deformed joints, significant motor impairment, visual defects, and CC sometimes cognitive deficits. Affected individuals typically have CC normal early development in the first year or so of life, followed by CC development regression and the development of symptoms. Brain imaging CC shows white matter abnormalities consistent with hypomyelinating CC leukodystrophy. {ECO:0000269|PubMed:28842795}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 6]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the FAD-dependent oxidoreductase family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAY84741.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44053/AIFM1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF100928; AAD16436.1; -; mRNA. DR EMBL; DQ016496; AAY84737.1; -; mRNA. DR EMBL; DQ016498; AAY84739.1; -; mRNA. DR EMBL; DQ016500; AAY84741.1; ALT_SEQ; mRNA. DR EMBL; AL049703; CAB41267.1; -; mRNA. DR EMBL; AL049704; CAB41268.1; -; mRNA. DR EMBL; AK314446; BAG37055.1; -; mRNA. DR EMBL; CR457379; CAG33660.1; -; mRNA. DR EMBL; AL139234; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF459397; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF510638; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471107; EAX11811.1; -; Genomic_DNA. DR EMBL; CH471107; EAX11812.1; -; Genomic_DNA. DR EMBL; CH471107; EAX11810.1; -; Genomic_DNA. DR EMBL; BC111065; AAI11066.1; -; mRNA. DR EMBL; BC139738; AAI39739.1; -; mRNA. DR EMBL; AF131759; AAD20036.1; -; mRNA. DR CCDS; CCDS14618.1; -. [O95831-1] DR CCDS; CCDS14619.1; -. [O95831-3] DR CCDS; CCDS48167.1; -. [O95831-4] DR RefSeq; NP_001124318.2; NM_001130846.3. DR RefSeq; NP_001124319.1; NM_001130847.3. [O95831-4] DR RefSeq; NP_004199.1; NM_004208.3. [O95831-1] DR RefSeq; NP_665811.1; NM_145812.2. [O95831-3] DR PDB; 1M6I; X-ray; 1.80 A; A=121-613. DR PDB; 4BUR; X-ray; 2.88 A; A/B/C/D=103-613. DR PDB; 4BV6; X-ray; 1.80 A; A=121-613. DR PDB; 4FDC; X-ray; 2.40 A; B=103-613. DR PDB; 4LII; X-ray; 1.88 A; A=100-611. DR PDB; 5FMH; X-ray; 1.80 A; A=104-613. DR PDB; 5FS6; X-ray; 1.90 A; A/B=103-613. DR PDB; 5FS7; X-ray; 1.85 A; A/B=103-613. DR PDB; 5FS8; X-ray; 1.40 A; A=103-613. DR PDB; 5FS9; X-ray; 1.75 A; A/B=103-613. DR PDB; 5KVH; X-ray; 2.27 A; A/B=78-613. DR PDB; 5KVI; X-ray; 2.00 A; A=78-613. DR PDB; 8D3E; X-ray; 2.38 A; A/B=78-613. DR PDB; 8D3G; X-ray; 2.58 A; A/B=78-613. DR PDB; 8D3H; X-ray; 2.51 A; A/B=78-613. DR PDB; 8D3I; X-ray; 2.65 A; A/B=78-613. DR PDB; 8D3J; X-ray; 2.40 A; A/B=78-613. DR PDB; 8D3K; X-ray; 2.30 A; A/B=78-613. DR PDB; 8D3N; X-ray; 2.25 A; A/B=78-613. DR PDB; 8D3O; X-ray; 2.25 A; A/B=78-613. DR PDBsum; 1M6I; -. DR PDBsum; 4BUR; -. DR PDBsum; 4BV6; -. DR PDBsum; 4FDC; -. DR PDBsum; 4LII; -. DR PDBsum; 5FMH; -. DR PDBsum; 5FS6; -. DR PDBsum; 5FS7; -. DR PDBsum; 5FS8; -. DR PDBsum; 5FS9; -. DR PDBsum; 5KVH; -. DR PDBsum; 5KVI; -. DR PDBsum; 8D3E; -. DR PDBsum; 8D3G; -. DR PDBsum; 8D3H; -. DR PDBsum; 8D3I; -. DR PDBsum; 8D3J; -. DR PDBsum; 8D3K; -. DR PDBsum; 8D3N; -. DR PDBsum; 8D3O; -. DR AlphaFoldDB; O95831; -. DR SMR; O95831; -. DR BioGRID; 114579; 626. DR CORUM; O95831; -. DR DIP; DIP-32975N; -. DR IntAct; O95831; 295. DR MINT; O95831; -. DR STRING; 9606.ENSP00000287295; -. DR ChEMBL; CHEMBL4295688; -. DR DrugBank; DB03147; Flavin adenine dinucleotide. DR DrugBank; DB05282; MCC. DR CarbonylDB; O95831; -. DR GlyCosmos; O95831; 1 site, 1 glycan. DR GlyGen; O95831; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O95831; -. DR MetOSite; O95831; -. DR PhosphoSitePlus; O95831; -. DR SwissPalm; O95831; -. DR BioMuta; AIFM1; -. DR REPRODUCTION-2DPAGE; IPI00157908; -. DR EPD; O95831; -. DR jPOST; O95831; -. DR MassIVE; O95831; -. DR MaxQB; O95831; -. DR PaxDb; 9606-ENSP00000287295; -. DR PeptideAtlas; O95831; -. DR ProteomicsDB; 51073; -. [O95831-1] DR ProteomicsDB; 51074; -. [O95831-2] DR ProteomicsDB; 51075; -. [O95831-3] DR ProteomicsDB; 51076; -. [O95831-4] DR ProteomicsDB; 61222; -. DR ProteomicsDB; 61439; -. DR Pumba; O95831; -. DR Antibodypedia; 3528; 956 antibodies from 47 providers. DR DNASU; 9131; -. DR Ensembl; ENST00000287295.8; ENSP00000287295.3; ENSG00000156709.15. [O95831-1] DR Ensembl; ENST00000346424.6; ENSP00000316320.3; ENSG00000156709.15. [O95831-2] DR Ensembl; ENST00000527892.5; ENSP00000435955.1; ENSG00000156709.15. [O95831-6] DR Ensembl; ENST00000535724.6; ENSP00000446113.2; ENSG00000156709.15. [O95831-4] DR Ensembl; ENST00000674997.1; ENSP00000502124.1; ENSG00000156709.15. [O95831-6] DR Ensembl; ENST00000675050.1; ENSP00000502606.1; ENSG00000156709.15. [O95831-3] DR Ensembl; ENST00000675774.1; ENSP00000502690.1; ENSG00000156709.15. [O95831-6] DR Ensembl; ENST00000676229.1; ENSP00000502184.1; ENSG00000156709.15. [O95831-3] DR GeneID; 9131; -. DR KEGG; hsa:9131; -. DR MANE-Select; ENST00000287295.8; ENSP00000287295.3; NM_004208.4; NP_004199.1. DR UCSC; uc004evg.4; human. [O95831-1] DR UCSC; uc065bbv.1; human. DR AGR; HGNC:8768; -. DR DisGeNET; 9131; -. DR GeneCards; AIFM1; -. DR GeneReviews; AIFM1; -. DR HGNC; HGNC:8768; AIFM1. DR HPA; ENSG00000156709; Low tissue specificity. DR MalaCards; AIFM1; -. DR MIM; 300169; gene. DR MIM; 300232; phenotype. DR MIM; 300614; phenotype. DR MIM; 300816; phenotype. DR MIM; 310490; phenotype. DR neXtProt; NX_O95831; -. DR OpenTargets; ENSG00000156709; -. DR Orphanet; 83629; Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome. DR Orphanet; 238329; Severe X-linked mitochondrial encephalomyopathy. DR Orphanet; 101078; X-linked Charcot-Marie-Tooth disease type 4. DR Orphanet; 139583; X-linked hereditary sensory and autonomic neuropathy with deafness. DR PharmGKB; PA162376129; -. DR VEuPathDB; HostDB:ENSG00000156709; -. DR eggNOG; KOG1346; Eukaryota. DR GeneTree; ENSGT00940000156455; -. DR HOGENOM; CLU_1059750_0_0_1; -. DR InParanoid; O95831; -. DR OMA; EVRYERC; -. DR OrthoDB; 74731at2759; -. DR PhylomeDB; O95831; -. DR TreeFam; TF314028; -. DR BioCyc; MetaCyc:ENSG00000156709-MONOMER; -. DR BRENDA; 7.1.1.2; 2681. DR PathwayCommons; O95831; -. DR SABIO-RK; O95831; -. DR SignaLink; O95831; -. DR SIGNOR; O95831; -. DR BioGRID-ORCS; 9131; 181 hits in 796 CRISPR screens. DR ChiTaRS; AIFM1; human. DR EvolutionaryTrace; O95831; -. DR GeneWiki; AIFM1; -. DR GenomeRNAi; 9131; -. DR Pharos; O95831; Tbio. DR PRO; PR:O95831; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; O95831; Protein. DR Bgee; ENSG00000156709; Expressed in apex of heart and 183 other cell types or tissues. DR ExpressionAtlas; O95831; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:UniProtKB. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0071949; F:FAD binding; IDA:UniProtKB. DR GO; GO:0016174; F:NAD(P)H oxidase H2O2-forming activity; IDA:UniProtKB. DR GO; GO:0003954; F:NADH dehydrogenase activity; IEA:RHEA. DR GO; GO:0016651; F:oxidoreductase activity, acting on NAD(P)H; IDA:UniProtKB. DR GO; GO:0072572; F:poly-ADP-D-ribose binding; ISS:UniProtKB. DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro. DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB. DR GO; GO:1904045; P:cellular response to aldosterone; IEA:Ensembl. DR GO; GO:0071392; P:cellular response to estradiol stimulus; IEA:Ensembl. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl. DR GO; GO:0071732; P:cellular response to nitric oxide; IEA:Ensembl. DR GO; GO:0030261; P:chromosome condensation; TAS:UniProtKB. DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:UniProtKB. DR GO; GO:0033108; P:mitochondrial respiratory chain complex assembly; IMP:UniProtKB. DR GO; GO:0032981; P:mitochondrial respiratory chain complex I assembly; IMP:UniProtKB. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0030182; P:neuron differentiation; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:0060545; P:positive regulation of necroptotic process; ISS:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0045041; P:protein import into mitochondrial intermembrane space; IMP:UniProtKB. DR GO; GO:1902510; P:regulation of apoptotic DNA fragmentation; IEA:Ensembl. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:1902065; P:response to L-glutamate; IEA:Ensembl. DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl. DR Gene3D; 3.30.390.30; -; 1. DR Gene3D; 3.50.50.60; FAD/NAD(P)-binding domain; 2. DR InterPro; IPR029324; AIF_C. DR InterPro; IPR036188; FAD/NAD-bd_sf. DR InterPro; IPR023753; FAD/NAD-binding_dom. DR InterPro; IPR016156; FAD/NAD-linked_Rdtase_dimer_sf. DR PANTHER; PTHR43557; APOPTOSIS-INDUCING FACTOR 1; 1. DR PANTHER; PTHR43557:SF4; APOPTOSIS-INDUCING FACTOR 1, MITOCHONDRIAL; 1. DR Pfam; PF14721; AIF_C; 1. DR Pfam; PF07992; Pyr_redox_2; 1. DR PRINTS; PR00368; FADPNR. DR PRINTS; PR00411; PNDRDTASEI. DR SMART; SM01353; AIF_C; 1. DR SUPFAM; SSF51905; FAD/NAD(P)-binding domain; 2. DR SUPFAM; SSF55424; FAD/NAD-linked reductases, dimerisation (C-terminal) domain; 1. DR UCD-2DPAGE; O95831; -. DR Genevisible; O95831; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Apoptosis; KW Charcot-Marie-Tooth disease; Cytoplasm; Deafness; KW Direct protein sequencing; Disease variant; DNA-binding; Dwarfism; FAD; KW Flavoprotein; Intellectual disability; Isopeptide bond; Membrane; KW Mitochondrion; Mitochondrion inner membrane; NAD; Neurodegeneration; KW Neuropathy; Nucleus; Oxidoreductase; Phosphoprotein; KW Primary mitochondrial disease; Reference proteome; Transit peptide; KW Ubl conjugation. FT TRANSIT 1..54 FT /note="Mitochondrion" FT /evidence="ECO:0000269|PubMed:15775970, FT ECO:0000269|PubMed:16365034, ECO:0007744|PubMed:25944712" FT PROPEP 55..101 FT /note="Removed in mature form" FT /evidence="ECO:0000269|PubMed:16365034" FT /id="PRO_0000401935" FT CHAIN 102..613 FT /note="Apoptosis-inducing factor 1, mitochondrial" FT /id="PRO_0000022030" FT REGION 100..127 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 134..483 FT /note="FAD-dependent oxidoreductase" FT /evidence="ECO:0000250" FT REGION 513..554 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 1..31 FT /note="Mitochondrial localization signal" FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1" FT MOTIF 63..89 FT /note="Mitochondrial localization signal" FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1" FT MOTIF 446..451 FT /note="Nuclear localization signal" FT /evidence="ECO:0000255" FT COMPBIAS 514..546 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 138..142 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, FT ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6, FT ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, FT ECO:0007744|PDB:5FS9, ECO:0007744|PDB:5KVI" FT BINDING 164..165 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, FT ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6, FT ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, FT ECO:0007744|PDB:5FS9, ECO:0007744|PDB:5KVH, FT ECO:0007744|PDB:5KVI" FT BINDING 172 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, FT ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6, FT ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, FT ECO:0007744|PDB:5FS9, ECO:0007744|PDB:5KVH, FT ECO:0007744|PDB:5KVI" FT BINDING 177 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:24914854, ECO:0000269|PubMed:27178839, FT ECO:0000269|PubMed:27818101, ECO:0007744|PDB:4BUR, FT ECO:0007744|PDB:4BV6, ECO:0007744|PDB:5FS7, FT ECO:0007744|PDB:5FS8, ECO:0007744|PDB:5FS9, FT ECO:0007744|PDB:5KVI" FT BINDING 196 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR" FT BINDING 233 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, FT ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6, FT ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, FT ECO:0007744|PDB:5FS9, ECO:0007744|PDB:5KVH, FT ECO:0007744|PDB:5KVI" FT BINDING 285 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, FT ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6, FT ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, FT ECO:0007744|PDB:5FS9, ECO:0007744|PDB:5KVH" FT BINDING 308..311 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR" FT BINDING 336 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR" FT BINDING 342 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1" FT BINDING 399 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR" FT BINDING 438 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, FT ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6, FT ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, FT ECO:0007744|PDB:5FS9, ECO:0007744|PDB:5KVH, FT ECO:0007744|PDB:5KVI" FT BINDING 453..454 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR" FT BINDING 454..455 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:24914854, ECO:0000269|PubMed:27178839, FT ECO:0000269|PubMed:27818101, ECO:0007744|PDB:4BUR, FT ECO:0007744|PDB:4BV6, ECO:0007744|PDB:5FS7, FT ECO:0007744|PDB:5FS8, ECO:0007744|PDB:5FS9, FT ECO:0007744|PDB:5KVH, ECO:0007744|PDB:5KVI" FT BINDING 483 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:12198487, FT ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:24914854, FT ECO:0000269|PubMed:27178839, ECO:0000269|PubMed:27818101, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6, FT ECO:0007744|PDB:5FS7, ECO:0007744|PDB:5FS8, FT ECO:0007744|PDB:5FS9, ECO:0007744|PDB:5KVH, FT ECO:0007744|PDB:5KVI" FT BINDING 483 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR, ECO:0007744|PDB:4BV6" FT BINDING 493 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR" FT BINDING 583 FT /ligand="NAD(+)" FT /ligand_id="ChEBI:CHEBI:57540" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:24914854, FT ECO:0007744|PDB:4BUR" FT MOD_RES 105 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:23186163" FT MOD_RES 109 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1" FT MOD_RES 116 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 118 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 268 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 292 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 371 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 388 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1" FT MOD_RES 521 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 524 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 530 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 593 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1" FT CROSSLNK 255 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:22103349" FT VAR_SEQ 1..352 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:16365034" FT /id="VSP_046248" FT VAR_SEQ 36..322 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_004357" FT VAR_SEQ 36..82 FT /note="GNLFQRWHVPLELQMTRQMASSGASGGKIDNSVLVLIVGLSTVGAGA -> V FT VQSHHLGSPSRSLASTGASGKDGSNLVYFLIVGATVTGAGVY (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4" FT /id="VSP_022953" FT VAR_SEQ 37..43 FT /note="NLFQRWH -> LQDYERG (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_060785" FT VAR_SEQ 44..613 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_060786" FT VAR_SEQ 323..324 FT /note="AR -> DI (in isoform 4)" FT /evidence="ECO:0000303|PubMed:16644725" FT /id="VSP_043637" FT VAR_SEQ 325..613 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:16644725" FT /id="VSP_043638" FT VARIANT 201 FT /note="Missing (in COXPD6; higher DNA binding affinity, FT partially impaired flavin binding and association with FT increased parthanatos-linked cell death; FT dbSNP:rs387906500)" FT /evidence="ECO:0000269|PubMed:20362274" FT /id="VAR_063827" FT VARIANT 235 FT /note="Q -> H (in SEMDHL; severe decrease of protein FT expression; dbSNP:rs377527583)" FT /evidence="ECO:0000269|PubMed:28842795" FT /id="VAR_083739" FT VARIANT 237 FT /note="D -> G (in SEMDHL; dbSNP:rs1202786652)" FT /evidence="ECO:0000269|PubMed:28842795" FT /id="VAR_083740" FT VARIANT 237 FT /note="D -> V (in SEMDHL; dbSNP:rs1202786652)" FT /evidence="ECO:0000269|PubMed:28842795" FT /id="VAR_083741" FT VARIANT 243 FT /note="V -> L (in COXPD6; reduced protein amount in muscle FT compared to controls; no effect on reduction with NADH; FT strongly decreased NADH oxidase activity; no effect on FT dimerization; no effect on DNA-binding; FT dbSNP:rs1603225138)" FT /evidence="ECO:0000269|PubMed:25583628, FT ECO:0000269|PubMed:27178839" FT /id="VAR_072791" FT VARIANT 260 FT /note="T -> A (in DFNX5; dbSNP:rs863225432)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076211" FT VARIANT 262 FT /note="G -> S (found in patient with mitochondrial FT encephalomyopathy with moderate clinical severity and slow FT progressive course despite early onset as well as and FT cerebellar involvement; likely pathogenic; decreased FT protein level; strongly decreased redox potential; strongly FT decreased NADH oxidase activity; no effect on DNA-binding; FT dbSNP:rs1603224817)" FT /evidence="ECO:0000269|PubMed:25934856, FT ECO:0000269|PubMed:27178839" FT /id="VAR_083067" FT VARIANT 308 FT /note="G -> E (in COXPD6; with prenatal ventriculomegaly FT and severe postnatal encephalomyopathy; no effect on redox FT potential; slowered reduction with NADH; strongly decreased FT NADH oxidase activity; strongly decreased NADH oxidase FT activity; no effect on DNA-binding; decreased interaction FT with CHCHDE; dbSNP:rs1603224226)" FT /evidence="ECO:0000269|PubMed:22019070, FT ECO:0000269|PubMed:26004228, ECO:0000269|PubMed:27178839" FT /id="VAR_067334" FT VARIANT 338 FT /note="G -> E (in COXPD6; with early-onset severe motor FT neuron involvement; decreased protein levels; decreased FT oxidoreductase activity on cytochrome C; slowered reduction FT with NADH; strongly decreased NADH oxidase activity; FT strongly decreased NADH oxidase activity; no effect on FT DNA-binding; dbSNP:rs1603223152)" FT /evidence="ECO:0000269|PubMed:26173962, FT ECO:0000269|PubMed:27178839" FT /id="VAR_083068" FT VARIANT 344 FT /note="L -> F (in DFNX5; uncertain significance; FT dbSNP:rs184474885)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076212" FT VARIANT 360 FT /note="G -> R (in DFNX5; uncertain significance; FT dbSNP:rs724160026)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076213" FT VARIANT 422 FT /note="R -> Q (in DFNX5; dbSNP:rs724160021)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076214" FT VARIANT 422 FT /note="R -> W (in DFNX5; dbSNP:rs724160020)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076215" FT VARIANT 430 FT /note="R -> C (in DFNX5; uncertain significance; FT dbSNP:rs1223488720)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076216" FT VARIANT 451 FT /note="R -> Q (in DFNX5; dbSNP:rs863225431)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076217" FT VARIANT 472 FT /note="A -> V (in DFNX5; uncertain significance)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076218" FT VARIANT 475 FT /note="P -> L (in DFNX5; uncertain significance; FT dbSNP:rs724160022)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076219" FT VARIANT 493 FT /note="E -> V (in CMTX4; increases affinity for NADH and FT electron transfer activity; increases affinity for DNA, FT resulting in increased apoptosis; no effect on interaction FT with CHCHD4; dbSNP:rs281864468)" FT /evidence="ECO:0000269|PubMed:23217327, FT ECO:0000269|PubMed:26004228" FT /id="VAR_069468" FT VARIANT 498 FT /note="V -> M (in DFNX5; uncertain significance; FT dbSNP:rs724160023)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076220" FT VARIANT 591 FT /note="I -> M (in DFNX5; uncertain significance)" FT /evidence="ECO:0000269|PubMed:25986071" FT /id="VAR_076221" FT MUTAGEN 196 FT /note="W->A: Increases protein dimerization at lower NADH FT levels." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 413..430 FT /note="EIDSDFGGFRVNAELQAR->AIDSDFGGFAVNAELQAA: Disrupts FT dimerization. Lower efficiency in stabilizing FT charge-transfer complexes upon coenzyme reduction." FT /evidence="ECO:0000269|PubMed:24914854" FT MUTAGEN 443..445 FT /note="YDI->ADA: Disrupts dimerization. Disrupts FT dimerization; when associated with A-477." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 454 FT /note="H->A: Allows dimerization in absence of NADH." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 477 FT /note="W->A: Disrupts dimerization; when associated with FT A-443--445-A." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 480 FT /note="S->A: Allows dimerization in absence of NADH." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 485 FT /note="D->A: Increases protein dimerization at lower NADH FT levels." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 529 FT /note="R->A: Increases protein dimerization at lower NADH FT levels." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 531 FT /note="E->A: Increases protein dimerization at lower NADH FT levels." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 533 FT /note="E->A: Increases protein dimerization at lower NADH FT levels." FT /evidence="ECO:0000269|PubMed:27818101" FT MUTAGEN 535 FT /note="E->A: Increases protein dimerization at lower NADH FT levels." FT /evidence="ECO:0000269|PubMed:27818101" FT STRAND 130..138 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 141..153 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 158..162 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 164..167 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 173..176 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 178..180 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 187..190 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 192..194 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 200..206 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 208..210 FT /evidence="ECO:0007829|PDB:5FS8" FT TURN 214..219 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 224..228 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 233..237 FT /evidence="ECO:0007829|PDB:5FS8" FT TURN 238..241 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 242..245 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 250..258 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 262..264 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 268..271 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 275..279 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 281..283 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 287..299 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 301..306 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 310..326 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 329..333 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 335..338 FT /evidence="ECO:0007829|PDB:5FS8" FT TURN 339..343 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 346..358 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 362..364 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 369..375 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 378..383 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 388..396 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 400..402 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 407..410 FT /evidence="ECO:0007829|PDB:5FS8" FT TURN 416..418 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 420..422 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 427..430 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 433..435 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 437..439 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 440..444 FT /evidence="ECO:0007829|PDB:5FS8" FT TURN 445..447 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 448..450 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 455..468 FT /evidence="ECO:0007829|PDB:5FS8" FT TURN 469..471 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 481..487 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 491..496 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 504..509 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 513..515 FT /evidence="ECO:0007829|PDB:4BUR" FT HELIX 517..524 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 529..533 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 538..542 FT /evidence="ECO:0007829|PDB:5KVI" FT STRAND 562..569 FT /evidence="ECO:0007829|PDB:5FS8" FT STRAND 572..580 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 585..594 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 601..605 FT /evidence="ECO:0007829|PDB:5FS8" FT HELIX 606..608 FT /evidence="ECO:0007829|PDB:5FS8" SQ SEQUENCE 613 AA; 66901 MW; A156762BC64E6340 CRC64; MFRCGGLAAG ALKQKLVPLV RTVCVRSPRQ RNRLPGNLFQ RWHVPLELQM TRQMASSGAS GGKIDNSVLV LIVGLSTVGA GAYAYKTMKE DEKRYNERIS GLGLTPEQKQ KKAALSASEG EEVPQDKAPS HVPFLLIGGG TAAFAAARSI RARDPGARVL IVSEDPELPY MRPPLSKELW FSDDPNVTKT LRFKQWNGKE RSIYFQPPSF YVSAQDLPHI ENGGVAVLTG KKVVQLDVRD NMVKLNDGSQ ITYEKCLIAT GGTPRSLSAI DRAGAEVKSR TTLFRKIGDF RSLEKISREV KSITIIGGGF LGSELACALG RKARALGTEV IQLFPEKGNM GKILPEYLSN WTMEKVRREG VKVMPNAIVQ SVGVSSGKLL IKLKDGRKVE TDHIVAAVGL EPNVELAKTG GLEIDSDFGG FRVNAELQAR SNIWVAGDAA CFYDIKLGRR RVEHHDHAVV SGRLAGENMT GAAKPYWHQS MFWSDLGPDV GYEAIGLVDS SLPTVGVFAK ATAQDNPKSA TEQSGTGIRS ESETESEASE ITIPPSTPAV PQAPVQGEDY GKGVIFYLRD KVVVGIVLWN IFNRMPIARK IIKDGEQHED LNEVAKLFNI HED //